ZAP70, SRK, STCD, STD, TZK, ZAP-70, zeta chain of T cell receptor associated protein kinase 70kDa, zeta chain of T cell receptor associated protein kinase 70, zeta chain of T-cell receptor associated protein kinase 70, IMD48, ADMIO2
ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells).[5] It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.
ZAP-70 was initially discovered in TCR-stimulated Jurkat cells, an immortal line of human T lymphocytes, in 1991.[6] Its molecular weight is 70 kDa, and it is a member of the protein-tyrosine kinase family and is a close homolog of SYK. SYK and ZAP70 share a common evolutionary origin and split from a common ancestor in the jawed vertebrates. [7]
The importance of ZAP-70 in T cell activation was determined when comparing ZAP-70 expression in patients with SCID (severe combined immunodeficiency).[6] ZAP-70 deficient individuals were found to have no functioning T cells in their peripheral blood, suggesting that ZAP-70 is a critical component of T cell activation and development.[6]
The T cell receptor has no innate enzymatic activity. Due to this, T cell receptors rely on signaling molecules to transduce a signal from the cell membrane. ZAP-70 is a critical cytoplasmic tyrosine kinase that initiates a signal pathway downstream of an activated T cell receptor.[8]
T lymphocytes are activated by engagement of the T cell receptor with processed antigen fragments presented by professional antigen presenting cells (i.e. macrophages, dendritic cells, Langerhans cells and B cells) via the MHC. Upon this activation, the TCR co-receptor CD4 (expressed on T helper cells) or CD8 (expressed on cytotoxic T cells) binds to the MHC, activating the co-receptor associated tyrosine kinase Lck. Lck is moved near the CD3 complex and phosphorylates the tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMS), creating a docking site for ZAP-70.[9] The most important member of the CD3 family is CD3-zeta, to which ZAP-70 binds (hence the abbreviation). The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta, which positions ZAP-70 to phosphorylate the transmembrane protein linker for activation of T cells (LAT).[9] Phosphorylated LAT, in turn, serves as a docking site to which a number of signaling proteins bind, including the SH2-domain-containing leukocyte protein of 76 kDa (SLP-76).[9] SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases.[10] The final outcome of T cell activation is the transcription of several gene products which allow the T cells to differentiate, proliferate, and secrete a number of cytokines.
Clinical Significance
Due to its role in lymphocyte signaling, ZAP-70 has been associated with several diseases affecting lymphocytes. ZAP-70 expression is a significant indicator of the survival of lymphocytes and has been notably associated with chronic lymphocytic leukemia (CLL).[11] CLL is a cancer that develops from overproduction of B cells in the bone marrow.
In people with CLL, higher levels of ZAP-70 confers a worse prognosis; CLL patients that are positive for the marker ZAP-70 have an average survival of 8 years, whereas those that are negative for ZAP-70 have an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.[12] In individuals with CLL, higher levels of ZAP-70 is associated with a higher number of malignant B cells activated.[5] Increased expression of ZAP-70 in B cell malignancies is correlated with increased association between malignant B cells and the immune environment, suggesting a complex role for ZAP-70 in B cell signaling.[5]
ZAP-70 deficiency results in a form of autosomal recessive immune deficiency named combined immunodeficiency.[14] Patients afflicted with combined immunodeficiency have a normal lymphocyte count, but they have low concentrations of T helper cells and cytotoxic T cells.[14] Patients were also found to have irregular lymphocyte proliferation responses.[14] These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions.[14]
^Chiorazzi N, Rai KR, Ferrarini M (February 2005). "Chronic lymphocytic leukemia". The New England Journal of Medicine. 352 (8): 804–15. doi:10.1056/NEJMra041720. PMID15728813.
^Tsokos GC (December 2011). "Systemic lupus erythematosus". The New England Journal of Medicine. 365 (22): 2110–21. doi:10.1056/NEJMra1100359. PMID22129255.
^ abcdShirkani A, Shahrooei M, Azizi G, Rokni-Zadeh H, Abolhassani H, Farrokhi S, et al. (January 2017). "Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature". Immunological Investigations. 46 (1): 70–79. doi:10.1080/08820139.2016.1214962. PMID27759478. S2CID30518855.
^Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, et al. (August 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry. 41 (34): 10732–40. doi:10.1021/bi025554o. PMID12186560.
^Lindholm CK, Henriksson ML, Hallberg B, Welsh M (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry. 269 (13): 3279–88. doi:10.1046/j.1432-1033.2002.03008.x. PMID12084069.
Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. doi:10.1016/0092-8674(92)90598-7. PMID1423621. S2CID54326428.
Hamblin AD, Hamblin TJ (December 2005). "Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia". Expert Opinion on Therapeutic Targets. 9 (6): 1165–78. doi:10.1517/14728222.9.6.1165. PMID16300468. S2CID20808988.
Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. doi:10.1016/0092-8674(92)90598-7. PMID1423621. S2CID54326428.
Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju S, Hatakeyama S, et al. (August 1995). "Essential role for ZAP-70 in both positive and negative selection of thymocytes". Nature. 376 (6539): 435–8. Bibcode:1995Natur.376..435N. doi:10.1038/376435a0. PMID7630421. S2CID4366344.
Mustelin T, Williams S, Tailor P, Couture C, Zenner G, Burn P, et al. (April 1995). "Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase". European Journal of Immunology. 25 (4): 942–6. doi:10.1002/eji.1830250413. PMID7737297. S2CID19309659.
Schumann G, Dasgupta JD (September 1994). "Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif". International Immunology. 6 (9): 1383–92. doi:10.1093/intimm/6.9.1383. PMID7819147.
Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans". Immunogenetics. 40 (4): 300–2. doi:10.1007/BF00189976. PMID8082894. S2CID33774157.
Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, et al. (May 1994). "Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling". Journal of Immunology. 152 (10): 4758–66. doi:10.4049/jimmunol.152.10.4758. PMID8176201. S2CID37831763.
Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG (June 1994). "Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase". Science. 264 (5165): 1596–9. Bibcode:1994Sci...264.1596E. doi:10.1126/science.8202712. PMID8202712.
Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, et al. (June 1994). "ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency". Science. 264 (5165): 1599–601. Bibcode:1994Sci...264.1599C. doi:10.1126/science.8202713. PMID8202713.
